DESCRIPTION Mitochondria are the main sources of energy in the cell. They are unique mammalian organelles because they contain their own DNA (mtDNA), whose genes encode components of the respiratory chain/oxidative phosphorylation system. They are essential for the normal functioning of all cells in the body, and are absolutely for the function of those tissues that are highly dependent on aerobic metabolism, including heart and skeletal muscle and brain. Since 1988, over 50 mtDNA point mutations have been reported. Of the 13 mtDNA point mutations in patients with clinically exclusive or predominant cardiomyopathy, six were identified by group. The applicant proposes to continue his studies of human cardiomyopathies along three lines of investigations. First he will screen patients for known and novel mtDNA mutations, focusing on patients with cardiomyopathies are maternally-inherited, sporadic hypertrophic, or associated with neurological features. Second, he will determine the molecular genetic defect in the Autosomal Recessive Cardiomyopathy Ophthalmoplegia (ARCO) syndrome associated with multiple mtDNA deletions. Understanding this disorder will likely promote our knowledge of the intergenomic communication between the nucleus and mitochondria. Third, he will study the effects to two different pathogenic mtDNAs that cause cardiomyopathy using the powerful cybrid tissue culture system which allows him to fuse cytoplasts containing a mtDNA mutation with rho cells which are devoid of mtDNA. Thus, he can study the in vitro consequences of a mtDNA mutation against a uniform nuclear DNA background. If attempts to an immortalized human cardiomyocyte cell line are successful, he will create cardiomyocyte cybrids to test tissue-specific effects of the mtDNA mutations. Through his proposed studies, he hopes to better understand the spectrum and the pathogenesis of mtDNA mutations in human cardiomyopathies.